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Association between schizophrenia and both loss of function and missense mutations in paralog conserved sites of voltage-gated sodium channels

View ORCID ProfileElliott Rees, Noa Carrera, Joanne Morgan, Kirsty Hambridge, Valentina Escott-Price, Andrew J. Pocklington, Alexander L. Richards, Antonio F. Pardiñas, GROUP Investigators, Colm McDonald, Gary Donohoe, Derek W Morris, Elaine Kenny, Eric Kelleher, Michael Gill, Aiden Corvin, George Kirov, James T. R. Walters, Peter Holmans, Michael J. Owen, Michael C. O’Donovan
doi: https://doi.org/10.1101/246850
Elliott Rees
1MRC Centre for Neuropsychiatric Genetics and Genomics, Division of Psychological Medicine and Clinical Neurosciences, School of Medicine, Cardiff University, Cardiff, UK
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  • ORCID record for Elliott Rees
Noa Carrera
1MRC Centre for Neuropsychiatric Genetics and Genomics, Division of Psychological Medicine and Clinical Neurosciences, School of Medicine, Cardiff University, Cardiff, UK
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Joanne Morgan
1MRC Centre for Neuropsychiatric Genetics and Genomics, Division of Psychological Medicine and Clinical Neurosciences, School of Medicine, Cardiff University, Cardiff, UK
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Kirsty Hambridge
1MRC Centre for Neuropsychiatric Genetics and Genomics, Division of Psychological Medicine and Clinical Neurosciences, School of Medicine, Cardiff University, Cardiff, UK
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Valentina Escott-Price
1MRC Centre for Neuropsychiatric Genetics and Genomics, Division of Psychological Medicine and Clinical Neurosciences, School of Medicine, Cardiff University, Cardiff, UK
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Andrew J. Pocklington
1MRC Centre for Neuropsychiatric Genetics and Genomics, Division of Psychological Medicine and Clinical Neurosciences, School of Medicine, Cardiff University, Cardiff, UK
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Alexander L. Richards
1MRC Centre for Neuropsychiatric Genetics and Genomics, Division of Psychological Medicine and Clinical Neurosciences, School of Medicine, Cardiff University, Cardiff, UK
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Antonio F. Pardiñas
1MRC Centre for Neuropsychiatric Genetics and Genomics, Division of Psychological Medicine and Clinical Neurosciences, School of Medicine, Cardiff University, Cardiff, UK
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Colm McDonald
2Centre for Neuroimaging and Cognitive Genomics (NICOG), National University of Ireland Galway, Galway, Ireland
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Gary Donohoe
2Centre for Neuroimaging and Cognitive Genomics (NICOG), National University of Ireland Galway, Galway, Ireland
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Derek W Morris
2Centre for Neuroimaging and Cognitive Genomics (NICOG), National University of Ireland Galway, Galway, Ireland
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Elaine Kenny
3Department of Psychiatry & Trinity Translational Medicine Institute, Trinity College Dublin, Dublin, Ireland
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Eric Kelleher
3Department of Psychiatry & Trinity Translational Medicine Institute, Trinity College Dublin, Dublin, Ireland
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Michael Gill
3Department of Psychiatry & Trinity Translational Medicine Institute, Trinity College Dublin, Dublin, Ireland
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Aiden Corvin
3Department of Psychiatry & Trinity Translational Medicine Institute, Trinity College Dublin, Dublin, Ireland
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George Kirov
1MRC Centre for Neuropsychiatric Genetics and Genomics, Division of Psychological Medicine and Clinical Neurosciences, School of Medicine, Cardiff University, Cardiff, UK
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James T. R. Walters
1MRC Centre for Neuropsychiatric Genetics and Genomics, Division of Psychological Medicine and Clinical Neurosciences, School of Medicine, Cardiff University, Cardiff, UK
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Peter Holmans
1MRC Centre for Neuropsychiatric Genetics and Genomics, Division of Psychological Medicine and Clinical Neurosciences, School of Medicine, Cardiff University, Cardiff, UK
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Michael J. Owen
1MRC Centre for Neuropsychiatric Genetics and Genomics, Division of Psychological Medicine and Clinical Neurosciences, School of Medicine, Cardiff University, Cardiff, UK
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  • For correspondence: OwenMJ@cardiff.ac.uk ODonovanMC@cardiff.ac.uk
Michael C. O’Donovan
1MRC Centre for Neuropsychiatric Genetics and Genomics, Division of Psychological Medicine and Clinical Neurosciences, School of Medicine, Cardiff University, Cardiff, UK
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  • For correspondence: OwenMJ@cardiff.ac.uk ODonovanMC@cardiff.ac.uk
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Abstract

Sequencing studies have highlighted candidate sets of genes involved in schizophrenia, including activity-regulated cytoskeleton-associated protein (ARC) and N-methyl-d-aspartate receptor (NMDAR) complexes. Two genes, SETD1A and RBM12, have also been associated with robust statistical evidence. Larger samples and novel methods for identifying disease-associated missense variants are needed to reveal novel genes and biological mechanisms associated with schizophrenia. We sequenced 187 genes, selected for prior evidence of association with schizophrenia, in a new dataset of 5,207 cases and 4,991 controls. Included were members of ARC and NMDAR post-synaptic protein complexes, as well as voltage-gated sodium and calcium channels. We observed a significant case excess of rare (<0.1% in frequency) loss-of-function (LoF) mutations across all 187 genes (OR = 1.36; Pcorrected = 0.0072) but no individual gene was associated with schizophrenia after correcting for multiple testing. We found novel evidence that LoF and missense variants at paralog conserved sites were enriched in sodium channels (OR = 1.26; P = 0.0035). Meta-analysis of our new data with published sequencing data (11,319 cases, 15,854 controls and 1,136 trios) supported and refined this association to sodium channel alpha subunits (P = 0.0029). Meta-analysis also confirmed association between schizophrenia and rare variants in ARC (P = 4.0 × 10−4) and NMDAR (P = 1.7 × 10−5) synaptic genes. No association was found between rare variants in calcium channels and schizophrenia.

In one of the largest sequencing studies of schizophrenia to date, we provide novel evidence that multiple voltage-gated sodium channels are involved in schizophrenia pathogenesis, and increase the evidence for association between rare variants in ARC and NMDAR post-synaptic complexes and schizophrenia. Larger samples are required to identify specific genes and variants driving these associations.

Author Summary Common and rare genetic variations are known to play a substantial role in the development of schizophrenia. Recently, sequencing studies have started to highlight specific sets of genes that are enriched for rare variation in schizophrenia, such as the synaptic gene sets ARC and NMDAR, as well as voltage-gated sodium and calcium channels. To confirm the role of these gene sets in schizophrenia, and identify specific risk genes, we sequenced 187 genes in a new sample of 5,207 schizophrenia cases and 4,991 controls. We find an excess of protein truncating mutations with a frequency <0.1% in all 187 targeted genes, and provide novel evidence that mutations altering amino acids conserved across sodium channel proteins are risk factors for schizophrenia. Through meta-analysing our new data with previously published sequencing data sets, for a total of 11,319 cases, 15,854 controls and 1,136 trios, we increase the evidence for association between rare coding variants and schizophrenia in voltage-gated sodium channels, as well as in synaptic gene sets ARC and NMDAR. Although no individual gene was associated with schizophrenia, these findings suggest larger studies will identify the specific genes driving these associations.

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted January 12, 2018.
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Association between schizophrenia and both loss of function and missense mutations in paralog conserved sites of voltage-gated sodium channels
Elliott Rees, Noa Carrera, Joanne Morgan, Kirsty Hambridge, Valentina Escott-Price, Andrew J. Pocklington, Alexander L. Richards, Antonio F. Pardiñas, GROUP Investigators, Colm McDonald, Gary Donohoe, Derek W Morris, Elaine Kenny, Eric Kelleher, Michael Gill, Aiden Corvin, George Kirov, James T. R. Walters, Peter Holmans, Michael J. Owen, Michael C. O’Donovan
bioRxiv 246850; doi: https://doi.org/10.1101/246850
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Association between schizophrenia and both loss of function and missense mutations in paralog conserved sites of voltage-gated sodium channels
Elliott Rees, Noa Carrera, Joanne Morgan, Kirsty Hambridge, Valentina Escott-Price, Andrew J. Pocklington, Alexander L. Richards, Antonio F. Pardiñas, GROUP Investigators, Colm McDonald, Gary Donohoe, Derek W Morris, Elaine Kenny, Eric Kelleher, Michael Gill, Aiden Corvin, George Kirov, James T. R. Walters, Peter Holmans, Michael J. Owen, Michael C. O’Donovan
bioRxiv 246850; doi: https://doi.org/10.1101/246850

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